Update on Benign Prostatic Hyperplasia William I. Jaffe, MD Assistant Professor of Urology in Surgery Penn Presbyterian Medical Center University of Pennsylvania Health System Nobel Prize Winners in Urology Werner Forssmann- 1956 Charles B. Huggins- 1966 Introduction • • • • • • Epidemiology Changes in Terminology Evaluation Medical Therapy Surgical Therapy BPH and Sex! A Modern View of BPH Clinical, Anatomic, and Pathophysiologic Changes • BPH = Benign Prostatic Hyperplasia – Histologic: stromoglandular hyperplasia1 All Men >50 y • May be associated with – Clinical: presence of bothersome LUTS2 – Anatomic: enlargement of the gland (BPE = Benign Prostatic Enlargement)2 – Pathophysiologic: compression of urethra and compromise of urinary flow (BOO = Bladder Outlet Obstruction)2 Histologic BPH BPE Enlargement ` BOO Obstruction LUTS/ Bother 1. American Urological Association Research and Education Inc. BPH Guidelines 2003. 2. Nordling J et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001:107166. Prevalence of BPH Versus Other Common Conditions BPH (Men Ages 61 to 72) Diabetes (Adults Over 65) Asthma (Entire Population) 0 25 50 Berry SJ, et al. J Urol. 1984;132:474-479. CDC. 2003 National Diabetes Fact Sheet. Available at http://www.cdc.gov/diabetes/pubs/estimates.htm. Accessed May 16, 2003. CDC. 1998 Forecasted State-Specific Estimates of Self-Reported Asthma Prevalence. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/00055803.htm. Accessed January 8, 2003. 75 Prevalence of Histologic BPH 100 90 Prevalence (%) 80 70 60 50 40 30 20 10 0 20–29 30–39 40–49 50–59 60–69 70–79 80–89 Age Pradhan 1975 Moore 1943 Baron 1941 Swyer 1944 Harbitz 1972 Fang-Liu 1991 Franks 1954 Holund 1980 Karube 1961 Natural History of BPH: Prostate Volume Increases • 631 white men ages 40 to 79 from Olmsted County, Minnesota • Prostate volume measured up to 4 times by transrectal ultrasound during a 7-year follow-up period • Estimated prostate growth rates increased by 1.6% per year across all ages • Higher baseline prostate volume associated with higher rates of prostate growth Rhodes T et al. J Urol. 1999;161:1174–1179. Collins GN et al. Br J Urol. 1993;71:445–450. Jacobsen SJ et al. Urology. 2001;58(Suppl 6A):5–16. Prevalence of Symptomatic BPH 9,000,000 8,000,000 7,000,000 Male Medicare patients (>65 y) with LUTS/BPH 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 0 1990 1.7 2000 2010 Weiner DM et al. Urology. 1997;49:335-342. 2020 40 450 400 350 300 250 200 150 100 50 0 Qmax (mL/sec) 35 30 25 20 15 10 5 0 40–44 45–49 50–54 55–59 60–64 65–69 70–74 Age Groups (y) Qmax Volume Roberts RO et al. J Urol. 2000;163:107–113. 75+ Volume (mL) Natural History of BPH: Qmax and Voided Volume Natural History of BPH: Risk of Acute Urinary Retention Increases 40 Incidence of Acute Urinary Retention (per 1000 person years) • 2115 white men ages 40 to 79 from Olmsted County, Minnesota • Symptoms measured via questionnaire • Incidence of acute urinary retention over 4 years ascertained via review of medical records • 8344 person-years of data obtained 34.7 35 30 25 20 15 9.3 10 5 2.6 3 0 40 to 49 years 70 to 79 years Mild to Moderate Symptoms Moderate to Severe Symptoms Jacobsen SJ et al. J Urol. 1997;158:481–487. 10-Year Probability of Surgery (% of Patients) Natural History of BPH: Risk of Surgery Increases 40 34 30 20 16 13 10 9 7 3 2 2 0 40–49 50–59 60–69 Age (y) Without prostatic enlargement and obstructive symptoms With prostatic enlargement and obstructive symptoms Arrighi HM et al. Urology. 1991;38(suppl):4–8. 70–79 PSA… It’s not just for cancer • • • • Serine protease produced by epithelial cells Dissolves semen coagulum Most bound to antiproteases ACT Increased with– Malignancy – Hyperplasia – Infection/Inflammation Serum PSA and Prostate Volume Increases Correlate with Age Roehrborn CG et al. J Urol. 2000;163:13-20. PSA as a Predictor of Future Prostate Growth % Change in PV at 48 Months Annualized Growth Rates Prostate Volume Roehrborn CG et al. J Urol. 2000;163:13-20. • Low PSA tertile: 0.7 mL/year • Middle PSA tertile: 2.1 mL/year • High PSA tertile: 3.3 mL/year Incidence of AUR and/or Surgery Over 4 Years by PSA Tertiles % Patients Left untreated 1 in 6 patients with a PSA of >1.4 ng/mL will experience AUR or BPH-related surgery over a 4-year time period Surgery/AUR Baseline PSA tertiles (ng/mL) Roehrborn CG et al. Urology. 1999;53:473-480. What is “BPH”? • “Prostatism” and “BPH” • Benign Prostatic Hyperplasia is a histological diagnosis • New Urological Lexicon Terminology BPH BPE BPO Histologic diagnosis Enlargement due to benign growth (can be without obstruction) Urodynamically proven BOO (static/dynamic components) BPH = benign prostatic hyperplasia; BPE = benign prostatic enlargement; BPO = benign 1.2prostatic obstruction; BOO = bladder outlet obstruction LUTS • Symptoms attributable to lower urinary tract dysfunction – storage (irritative) symptoms – emptying (obstructive) symptoms – may be associated with BPH, BPE, and BPO, but not exclusive to these Nordling J et al. Benign Prostatic Hyperplasia. 5th International Consultation 1.4Benign Prostatic Hyperplasia. Paris, France. June 25-28, 2000:107-166. on OAB: US Prevalence by Age 40 Men Prevalence (%) 35 Women 30 25 20 15 10 5 0 18-24 25-34 35-44 45-54 55-64 Age (years) OAB=overactive bladder. Stewart W, et al. World J Urol. 2003;20:327-336. 65-74 75+ Differential Diagnosis • Urethral stricture • • Bladder neck • contracture • • Bladder stones • • Urinary tract infection • • Interstitial cystitis 1.8 Neurogenic bladder Inflammatory prostatitis Medications Carcinoma of the prostate Carcinoma in situ of the bladder Old Paradigm Small prostate, thin bladder wall 2.2 Enlarged prostate, thick bladder wall Subsequent Paradigm Normal prostate Enlarged prostate 2.3 Small prostate with -receptors Brain/ Spinal column/ Prostate 2.4 -receptors Enlarged Normal Current Paradigm BPH/LUTS Pathophysiology Initial Evaluation • Detailed medical history • Physical exam – including DRE and neurologic exam • • • • Urinalysis Serum creatinine no longer mandatory PSA* Symptom assessment (AUA-SS) PSA = prostate-specific antigen *Per physician’s clinical judgment AUA BPH Guidelines 2003 4.4 Evaluation (Part 1) Initial evaluation • History • DRE & focused exam • Urinalysis • PSA1 Objective Symptom Assessment Mild IPSS7 Moderate to severe IPSS8 Offer treatment alternatives Watchful waiting Medical therapy Minimally invasive therapies Cystoscopy, if important in planning operative approach 1Optional in AHCPR Guidelines; Recommended by International Consensus Committee 4.2 Clinical Practice Guideline, Number 8. AHCPR Publication No. 94-0582. Surgery Evaluation (Part 2) Initial evaluation • History • DRE & focused exam • Urinalysis • PSA1 Objective Symptom Assessment Moderate to severe IPSS8 Additional diagnostic tests •Flow rate test1 •Residual urine1 •Pressure-flow2 Compatible with obstruction 1Optional Not compatible with obstruction Surgery Non-BPH problems identified and treated in AHCPR Guidelines; Recommended by International Consensus Committee 2Optional in both AHCPR and International Consensus recommendations 4.3 Presence of: • Refractory retention Any of the following clearly 2° BPH: • Recurrent or persistent gross hematuria • Bladder stones • Renal insufficiency Goals of Therapy for BPH BPH Treatment Success measured by: • • • • • • ↓ symptoms (IPSS/AUA) ↓ bother (bother score) and ↑ QOL ↓ prostate size or arrest further growth ↑Increase in peak flow rate / Relieve obstruction Prevention of long-term outcomes/complications Acceptable adverse events profile US Agency for Health Care Policy and Research. AHCPR publication 94-0582; O’Leary MP. Urology. 2000;56(suppl 5A):7-11. Medical Treatments for BPH, LUTS, BOO – -adrenergic blockers – Dynamic – component 5 -reductase inhibitors – Anatomic – component Anticholinergic Therapy – Storage Sx’s Role of 1-Adrenoreceptors 1-ARs and Human LUTS Prostate Spinal cord Detrusor Vessels Smooth muscle contraction 1A Lumbosacral Instability Irritative symptoms 1D>1A Resistance vessels 1A Aging effects 1B>1A 1D Schwinn DA. BJU Int. 2000;86:11-22. Jardin A et al. Benign Prostatic Hyperplasia. 5th International Consultation on Benign Prostatic Hyperplasia. Paris, France. June 25-28, 2000:459-477. Rudner XL et al. Circ. 1999;100:2336-2343. 2.8 Comparison of -Adrenergic Blockers Agent Dosing Titration Uroselective Terazosin (Hytrin®) 1 mg, 2 mg, 5 mg, 10 mg, 20 mg + NO Doxazosin (Cardura®) 1 mg, 2 mg, 4 mg, 8 mg, 16 mg + NO Tamsulosin (Flomax®) 0.4 mg, 0.8 mg +/(for improved efficacy) YES (Relative affinity for 1A receptors over 1B ) Alfuzosin 10 mg - YES (Highly diffused in prostatic tissue vs serum) 1. HytrinR (terazosin hydrochloride) Prescribing information, Abbott Laboratories. 2. CarduraR (doxazosin mesylate tablets) Prescribing Information, Pfizer Inc. 3. FlomaxR (tamsulosin hydrochloride) Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc. 4. UroxatralR (alfuzosin HCl extended release tablets) Prescribing Information, Sanofi-Synthelabo Inc. Tamsulosin: Clinical Efficacy Tamsulosin 1.79 * 1.78 1.75 * * 1.52 Mean Change in Qmax (mL/s) 0 Placebo 0.93 1 0.52 0 Mean Change in Symptom Score 2 -2 -4 Study 2 (13 wk; 0.8 mg, 0.4 mg) *P0.05 statistically significant difference from placebo. Tamsulosin Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc.; 2003. -5.5 -6 * -5.8 * -5.1 -8 -10 Study 1 (13 wk; 0.8 mg, 0.4 mg) -3.60 * -8.3 * -9.6 Study 1 (13 wk; 0.8 mg, 0.4 mg) Study 2 (13 wk; 0.8 mg, 0.4 mg) N=1,486 Dihydrotestosterone (DHT) Action • Testosterone is converted to DHT by two 5reductase isoenzymes • The target for DHT is the androgen receptor • DHT has approximately 5 times greater affinity for the androgen receptor than testosterone • The greater affinity makes DHT a more potent androgenic steroid at physiologic concentrations • The DHT/androgen receptor complex alters gene expression Krieg M. Prog Cancer Res Ther. 1984;31:425–440. Kyprianou N et al. Prostate. 1986;8:363–380. Grino PB et al. Endocrinology. 1990;126:1165–1172. Clinical Efficacy of 5-ARIs Finasteride1 48-Mo Controlled Trial in 3040 Men Dutasteride2 24-Mo Controlled Trial in 4325 Men Finasteride Placebo Dutasteride Placebo Volume changes -18% +14% -26% -2% IPSS reduction -3.3 -1.3 -4.5 -2.3 Qmax improvement +1.9 +0.2 +2.2 +0.6 AUR risk reduction 57% 57% Surgery risk reduction 55% 48% *Not from a comparative trial. 1. McConnell JD et al. NEJM. 1998;338:557-563. 2. Roehrborn C et al. Urology. 2002;60:434-441. Adverse Events Finasteride1 Dutasteride2 Finasteride Placebo Dutasteride Placebo Erectile dysfunction 8 4 7 4 Altered libido 6 3 4 2 Ejaculatory disorder 4 1 2 1 Gynecomastia and breast tenderness 1 0.2 2 1 The new 5 alpha-reductase inhibitor Dutasteride has been shown to be of similar efficacy as Finasteride in terms of symptom score and flow-rate improvement, as well as in the prevention of disease progression, while having a comparable safety profile.3 *Not from a comparative trial. 1. McConnell JD et al. NEJM. 1998;338:557-563. 2. Roehrborn C et al. Urology. 2002;60:434-441. 3. American Urological Association Research and Education Inc. BPH Guidelines April 2003: page 33 Rationale for Combination Therapy 5-Reductase Inhibitors: Arrest Disease Progression AlphaBlockers: Relieve Symptoms Rapidly Combination Therapy: Arrest Disease Progression and Rapidly Relieve Symptoms MTOPS (Medical Treatment of Prostatic Symptoms) & Combination Therapy MTOPS Doxazosin/Finasteride/Combination • Double-masked, randomized, placebocontrolled, multicenter study • 3047 men aged 50 years with BPH • Average follow-up: 4.5 years • Primary outcome: time to clinical progression – – – – – AUR Renal insufficiency due to BPH Recurrent UTI or urosepsis Incontinence 4-point rise in baseline AUA symptom score confirmed within 2-4 weeks • Secondary outcomes – Changes in symptom and flow rate over time – Rate of invasive therapies for LUTS/BPH MTOPS = Medical Therapy Of Prostatic Symptoms. McConnell JD et al. NEJM, 2003. Cumulative Incidence of BPH Progression P<.0001; df=3 25 Placebo Event (%) 20 Finasteride: Risk Reduction = 34% 15 Doxazosin: Risk Reduction = 39% 10 Combination: Risk Reduction = 67% 5 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years From Randomization McConnell JD et al. NEJM, 2003. 4.0 4.5 5.0 5.5 Cumulative Incidence of AUR 4.0 3.5 P<.0034; df=3 Event (%) 3.0 Placebo 2.5 Doxazosin: Risk Reduction 2.0 1.5 Finasteride: Risk Reduction = 67% 1.0 0.5 Combination: Risk Reduction = 79% 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years From Randomization McConnell JD et al. NEJM, 2003. 4.0 4.5 5.0 5.5 Cumulative Incidence of BPH-Related Surgery 10 P<.0001; df=3 Event (%) 8 Doxazosin: Risk Reduction = 0% 6 Placebo 4 Finasteride: Risk Reduction = 64% 2 Combination: Risk Reduction = 67% 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Years From Randomization McConnell JD et al. NEJM, 2003. MTOPS Conclusions • In selected patients, combination therapy is most effective in – Reducing risk of clinical progression – Improving AUA symptom score – Improving maximum urinary flow rate • Monotherapy significantly reduces risk of clinical progression of BPH • Finasteride (5ARI) and combination therapy significantly reduce the risk of AUR and invasive therapy • Doxazosin (-adrenergic blocker) prolongs time to progression of AUR and invasive therapy, but does not reduce overall risk • Both long-term monotherapy and combination therapy are safe and effective McConnell J et al. Program Abstracts of the American Urological Association 2002 Annual Meeting (Abstract 1042, updated). Combination Treatment with An -Blocker Plus An Anticholinergic for Bladder Outlet Obstruction: A Prospective, Randomized, Controlled Study Athanasopoulos A, Gyftopoulos K, Giannitsas K, Fisfis J, Perimenis P, Barbalias G. J Urol. 2003;169:2253-2256 Detrol® and Tamsulosin Combination Therapy in Men With BOO and OAB • Randomized, controlled trial (independent research) – – – – 50 men 52 to 80 years of age (average, 69 years) Mild/moderate BOO on PFS Concomitant IDO • Study design – Complete QoL 9 UROLIFE questionnaire prior to study onset – 1-week tamsulosin 0.4 mg qd, then randomized to receive concomitant Detrol® 2 mg bid or continue tamsulosin monotherapy – Repeat QoL 9 and PFS at 12 weeks IDO=idiopathic detrusor overactivity; PFS=pressure flow studies. Athanasopoulos A, et al. J Urol. 2003;169:2253-2256. Detrol® and Tamsulosin Combination Therapy in Men with BOO and OAB: Effects on Urodynamic Parameters Tamsulosin (n = 25) Tamsulosin+Tolterodine (n = 25) Mean Change from Baseline P Value Mean Change from Baseline P Value Maximum detrusor pressure (cm H2O) –5.2 0.0827 –8.24 0.0082 Maximum flow rate (mL/second) +1.16 0.0001 +1.32 0.0020 Pressure at maximum unstable contraction (cm H2O) –2.16 0.05690 –11.16 0.0001 Volume at first unstable contraction (mL) +30.40 0.0190 +100.40 0.0001 Athanasopoulos A et al. J Urol. 2003;169:2253-6. Mean score (QoL 9 UROLIFE) Improved QoL Detrol® and Tamsulosin Therapy in Men With BOO and OAB: Effects on QoL 628.4 640 P=0.0003 620 600 P=NS 580 560 542.2 548.2 540 525 520 500 480 460 Baseline 12 Weeks Tamsulosin (n=25) Tamsulosin + Detrol® (n=25) Athanasopoulos A, et al. J Urol. 2003;169:2253-2256. Detrol® and Tamsulosin Therapy in Men With BOO and OAB: Conclusions • Efficacy – Improved QoL – Increased bladder capacity • Safety – No acute urinary retention was observed – Did not affect quality of urinary flow – Did not affect postvoid residual urine volume • “The proposed combination of Detrol® and tamsulosin appears to be an effective and relatively safe treatment option in patients with bladder outlet obstruction and detrusor overactivity” Athanasopoulos A, et al. J Urol. 2003;169:2253-2256. Surgical Therapy Indications for Surgery Relative Absolute • None • • • • • • • Symptoms Pt. Choice AUR Bleeding Bladder Calculus UTI Renal Insufficiency Alphabet Soup Electrosurgical TURP TUVP Laser Minimally-Invasive Gyrus PVP TUMT TUIP HoLAP TUNA HoLEP WIT ILC TEAP Open CLAP Botox Suprapubic VLAP ILC Retropubic Perineal Transurethral Resection of the Prostate (TURP): Overview Advantages • Availability of longterm outcomes data • Good clinical results • Treats prostates <150 g • Low retreatment rate • Low mortality Disadvantages • Retrograde ejaculation • Bleeding • TUR Syndrome • Catheter time • Hospital Stay Borth CS et al. Urology. 2001;57:1082-1086. Mebust WK et al. J Urol. 1989;141:243-247. Wagner JR et al. Semin Surg Oncol. 2000;18:216-228. 7.21 TURP: Efficacy • Symptom improvement in 88% of patients • 82% decrease in AUA Symptom Score • 125% improvement in peak flow rate (Qmax) • Re-op rate approx. 1.5%/yr Jepsen JV et al. Urology. 1998;51(suppl 4A):23-31. 7.22 TURP: Complications Clot Retention 16% Urethral Stricture 8.4% Transfusions 7.0% TUR Syndrome 0.9% Incontinence 1.3% Hoffman RM, et al: J Urol 2003. 169: 210-215 BPH, LUTS & SEX • LUTS and ED are common in middle age and older men • Sexual function is an important aspect of quality of life - sexual activity decreases with age - sexual problems increase with age BPH, LUTS & SEX • Erectile dysfunction is often associated with chronic diseases (i.e. diabetes, hypertension, … ) •25% of men over 60 years have BPH and HTN (4) • Recent community-based studies have shown a possible relationship between LUTS and sexual dysfunction (1,2,3) (1) Mc Farlane et al. - J.Clin.Epidemiol. 1996; 49:1171-76 (2) Franckel et al. - J.Clin.Epidemiol. 1998; 51:677-68 (3) Braun et al. - International Journal of Impotence Research 2000; 12:305-311 (4) Flack.Int. J. Clinical Practice 2002; 56(7): 527-530 Are they related? ● Affects similarly aged populations ● All have significant negative impact upon quality of life ● Association versus Pathophysiologic link? ● Proof of link requires robust epidemiologic data analyzing a large cohort of a representative population in a cross-sectional fashion BPH and Sexual Dysfunction • Chances of developing BPH and/or sexual dysfunction increase with age – sympathetic overreactivity • Treatments may cause sexual dysfunction – erectile dysfunction (ED) – altered ejaculation • Treatments should be tailored according to QOL and sexual function issues QOL = quality of life 3.3 DaSilva FC et al. Eur Urol. 1997;31:272-280. Zlotta AR et al. Eur Urol. 1999;36(suppl 1):107-112. MSAM-7 Objectives: • To evaluate in a population of men aged 50 to 80 years - The incidence of LUTS - The sexuality and the incidence of sexual disorders - The possible relationship between LUTS, sexual dysfunction, and co-morbid medical conditions MSAM-7 Methodology: •Patients - 14,000 men aged 50 to 80 in 7 countries (US, UK, F, D, I, Sp, NL) - In each country, the sample was representative of the target population MSAM-7 Methodology: • Postal questionnaire • - Demographic characteristics - I-PSS and Quality of Life index - Dan-PSS sex (6 questions) - IIEF (15 questions) - Co-morbidity factors • 12,815 questionnaire were exploitable (89.9%) Average Number of Sexual Intercourse or Activity per Month Base: Total sample 10 9 8 7 6 5 4 3 2 1 0 5.8 6.0 6.3 5.4 6.5 6.5 5.3 5.6 5.8 65 Average Number of Sexual Intercourse or Activity per Month Base: Total sample 10 9 8 7 6 5 4 3 2 1 0 8.6 7.6 6.6 5.7 4.9 5.7 4.6 3.7 4.0 3.5 2.6 1.7 LUTS 50 - 59 years 60 - 69 years 70 - 79 years 66 MSAM-7: Sex Declined With Increasing Severity of LUTS Average Number of Sexual Activities per Month* 10 9 8 7 8.6 7.6 LUTS 6.6 None Mild Moderate Severe 5.7 5.7 6 4.9 5 4.6 3.7 4 3 4.0 3.5 2.6 1.7 2 1 0 50-59 N=12,815 (total sample) *Among total sample. Rosen R et al. Eur Urol. 2003; 44:637-649. 60-69 Age (years) 70-79 MSAM-7 Average Erectile Function Score (IIEF)* ED Increased With Increasing Severity of LUTS Average score on a scale from 1 to 30 (6 questions) measured by IIEF Per question: 1 = Negative to 5 = Positive 30 22.3 20 LUTS 21.0 18.9 19.3 15.0 18.3 15.9 15.2 12.6 13.2 10.3 10 7.5 0 50-59 60-69 Age (years) Base: Men sexually active/sexual intercourse during past 4 weeks (n=9099) *as measured by IIEF. Rosen R et al. Eur Urol. 2003; 44:637-649. 70-79 None Mild Moderate Severe Mechanisms for Co-existence of ED and BPH ● Diminished quality of life theory ● Increased sympathetic tone theory ● Ischemia/Endothelial Dysfunction ● NO alteration theory Sildenafil Citrate Improves LUTS Mulhall et al, 2002 ● Men (n=30) presenting with ED and LUTS (IPSS 10) ● No prior or current alpha-blocker therapy ● Treated with Viagra (standard fashion) ● Sequential assessment of IIEF and IPSS ● Statistically significant improvement in IPSS on Viagra Tadalafil for BPH/LUTS Take-Home Messages • • • • • Aging Population= More BPH Not all Male LUTS=BPH Not all BPH=LUTS Consider Combination Therapy Quality of life issues